Proteasome is a multicatalytic protease complex that plays a critical role in mediating the regulated degradation of intracellular proteins. In vivo, the proteasome complex is believed to exist as 26S proteasome, which is about 2000 kDa in molecular weight and consists of one 20S core particle (20S proteasome) and two 19S regulatory particles. The core is hollow and provides an enclosed cavity in which proteins are degraded. Each end of the core particle associates with a 19S regulatory subunit that contains multiple ATPase active sites and ubiquitin binding sites, which recognizes polyubiquitinated proteins and transfers them to the catalytic core. An alternative form of regulatory subunit called the 11S particle associates with the core in essentially the same manner as the 19S particle; the 11S may play a role in degradation of foreign peptides. The core particle 20S proteasome is about 700 kDa in molecular weight and is comprised of 28 subunits organized into four rings. In yeast and other eukaryotes, 7α subunits form each of the two outer rings and 7β subunits form each of the two inner rings. The α rings serve as binding sites for the 19S or 11S regulatory complex, as well as a physical barrier for the two inner β rings. The two inner β rings contain active proteolytic sites. Degradation of proteins occurs within the central chamber formed by the association of the two β rings. In vivo, inhibition of the 20S proteasome can be directly correlated to inhibition of the 26S proteasome. There are two forms of proteasomes: the constitutive proteasome ubiquitously expressed by the majority of cells in the body, and the immunoproteasome, predominantly expressed in hematopoietic cells and cells that have been exposed to inflammatory cytokines. Proteasome-mediated protein degradation is a highly regulated process that is necessary for a variety of intracellular processes. Through the use of different peptide substrates, three major proteolytic activities have been defined for the eukaryote proteasome: chymotrypsin-like activity (CT-L), which cleaves after large hydrophobic residues; trypsin-like activity (T-L), which cleaves after basic residues; and peptidylglutamyl peptide hydrolyzing activity (PGPH), which cleaves after acidic residues. Proteasome has long been recognized as an attractive target for drug development, and was first clinically validated as a therapeutic target in oncology (Orlowski and Kuhn, Clin. Cancer Res. (2008), 14, 1649-1657).
Several small molecules have been used to inhibit proteasome activity, including peptide boronic acids, β-lactones and peptide epoxyketones (Bennett and Kirk, Current Opinion in Drug Discovery & Development (2008), 11, 616-625; Borissenko and Groll, Chem. Rev. (2007) 107, 687-717). However, these compounds generally lack appropriate specificity and/or potency necessary to fully explore and exploit the roles of proteasome at molecular, cellular and in vivo level. For example, peptide boronic acids and β-lactones are non-specific for proteasome, as they have been found to inhibit other proteases (Borissenko and Groll, Chem. Rev. (2007) 107, 687-717; Myung et al., Medicinal Research Reviews (2001), 21, 245-273). This raises the possibility that these inhibitors could exhibit off-target activities in vivo that are associated with inhibition of non-proteasome targets. On the other hand, the peptide epoxyketones as disclosed in U.S. Pat. No. 8,088,741B2, U.S. Pat. No. 6,831,099B1, WO2005/105827, CN101044157A, U.S. Pat. No. 7,687,452B2 and US2007/0105786A1 are highly selective as inhibitors of proteasomes. However, these peptide epoxyketones have poor aqueous solubility and/or less optimal proteasome inhibitory potency. Therefore, there are needs in the art to develop novel proteasome inhibitors that have improved pharmaceutical and/or biological properties.